Journal
CELL REPORTS
Volume 35, Issue 13, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109298
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Funding
- Arizona Biomedical Research Commission Early Stage Investigator Award [ADHS14-082986]
- American Heart Association Beginning Grant [15BGIA25090300]
- Arizona Biomedical Research Commission Investigator Grant [ADHS18201472]
- Cardiovascular Research (HLB) NIH T32 Training Grant [T32HL007249]
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Hepatic lipid accumulation in obesity leads to hyperinsulinemia and insulin resistance, which can be influenced by GABA release and communication between the liver and the vagal nerve. GABA dysregulation in obesity plays a role in glucoregulatory dysfunction.
Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity.
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